Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Cell Death Dis. 2020 Apr 8;11(4):226. doi: 10.1038/s41419-020-2429-9.
An imbalance in mitochondrial dynamics induced by oxidative stress may lead to hepatocyte epithelial mesenchymal transition (EMT) and liver fibrosis. However, the underlying molecular mechanisms have not been fully elucidated. This study investigated the role of mitochondrial dynamics in hepatocyte EMT and liver fibrosis using an in vitro human (L-02 cells, hepatic cell line) and an in vivo mouse model of liver fibrosis. Findings showed that oxidative stress-induced mitochondrial DNA damage was associated with abnormal mitochondrial fission and hepatocyte EMT. The reactive oxygen species (ROS) scavengers apocynin and mito-tempo effectively attenuated carbon tetrachloride (CCl)-induced abnormal mitochondrial fission and liver fibrosis. Restoring mitochondrial biogenesis attenuated hepatocyte EMT. Oxidative stress-induced abnormal hepatocyte mitochondrial fission events by a mechanism that involved the down regulation of PGC-1α. PGC-1α knockout mice challenged with CCl had increased abnormal mitochondrial fission and more severe liver fibrosis than wild type mice. These results indicate that PGC-1α has a protective role in oxidative stress-induced-hepatocyte EMT and liver fibrosis.
氧化应激引起的线粒体动力学失衡可能导致肝细胞上皮间质转化（EMT）和肝纤维化。然而，其潜在的分子机制尚未完全阐明。本研究使用体外人（L-02 细胞，肝细胞系）和体内小鼠肝纤维化模型探讨了线粒体动力学在肝细胞 EMT 和肝纤维化中的作用。结果表明，氧化应激诱导的线粒体 DNA 损伤与异常的线粒体分裂和肝细胞 EMT 有关。活性氧（ROS）清除剂 apocynin 和 mito-tempo 可有效减轻四氯化碳（CCl）诱导的异常线粒体分裂和肝纤维化。恢复线粒体生物发生可减轻肝细胞 EMT。氧化应激通过下调 PGC-1α 诱导异常的肝细胞线粒体分裂事件。用 CCl 处理的 PGC-1α 敲除小鼠比野生型小鼠有更多的异常线粒体分裂和更严重的肝纤维化。这些结果表明 PGC-1α 在氧化应激诱导的肝细胞 EMT 和肝纤维化中具有保护作用。
